A current hypothesis of the pathophysiology of schizophrenia posits two distinct changes in forebrain dopamine systems: 1)a decrease in functional dopamine activity in cortical regions that results in 2)an increase in dopamine tone in subcortical sites. We have shown that disruption of the prefrontal cortical dopamine (DA) system enhances the responsiveness of the ventral striatal dopaminergic innervation to environmental and pharmacological challenges. However, our data suggest that manipulations of DA in only certain cytoarchitectonic regions of the PFC can modify subcortical DA function. These observations suggest the presence of different mesoprefrontal cortical DA innervations. We hypothesize that there are multiple DA innervations of the medial PFC of the rat that can be anatomically and functionally dissociated. We suggest that DA release in the PFC regulates pyramidal (projection) neurons both directly and indirectly, the latter acting through GABAergic interneurons. We posit that the transsynaptic regulation of subcortical DA systems involves distinct regions of the PFC that give rise to parallel cortico-striato- fugal circuits that are interactive, and that can be functionally dissociated on the basis of responsiveness to stress and antipsychotic drugs. These hypotheses will be directly tested. We will determine if multiple prefrontal cortical DA innervations can be distinguished on the basis of anatomical criteria (source of dopamine afferents, coexistence of these sources with neuropeptides), pharmacological criteria (tyrosine hydroxylase mRNA levels, dopamine transporter mRNA levels, tyrosine hydroxylase phosphorylation state) and functional responsiveness (to stress and antipsychotic drug treatments). We will characterize dopaminergic regulation of GABA function in the PFC by examining extracellular GABA levels using in vivo microdialysis; correlative studies will assess the effects of chronic manipulations of PFC DA systems on glutamic acid decarboxylase mRNAs and protein levels, using in situ hybridization histochemistry and Northern blot analyses and Western blot analyses. Finally, we will examine the presence of parallel but functionally interactive cortico-striato-pallidal-mesencephalic-cortical circuits that subserve different functions. This will be accomplished by defining the anatomical arrangements between the different sites and by examining DA release and utilization and immediate early gene expression in response to stress and antipsychotic drugs. These studies may allow the definition of particular extended circuits at which stress acts to exacerbate the psychotic process in schizophrenia and at which antipsychotic drugs exert their therapeutic effects. These studies may also shed light on the corticostriatal circuits that are of importance in Parkinson's disease.